Post Tagged with: "Natural product synthesis"

From Natural Product to Pharmaceutical.

In a recent discussion (Nicolau), about the suggested move of Prof. NicoIau from Scripps, the issue of the practicality of natural product total synthesis was raised. Here is a wonderful example of just that very usefulness, a wonderful piece of science extending over many years. It concerns the journey from Halichondrin B to Eribulin (E7389) a novel anti-cancer drug. The two compounds have the following structures:

 

I think you can see the relationship and as a development chemist I am glad they managed to simplify things (a bit).

Both compounds have an enormous number of possible isomers: Halichondrin B, with 32 stereocenters has 232 possible isomers; Eribulin has 19 with 219 isomers (if I have counted correctly, it does not really matter, there are lots of isomers). Remarkable is the fact that only one of these isomers is active in the given area of anti-cancer agents.

An excellent review of the biology and chemistry of these compounds has been published by Phillips etal1. This review is an excellent read and is to be commended. Another one written by Kishi2, is also full of information about the discovery of E7389 and I hope you will all get a chance to read this chapter.

The history of Halichondrin B goes back to 1987 when Blunt2-5 isolated it with other similar compounds from extraction of 200Kg of a sponge. Independently Pettit isolated the same compound from a different species4. The appearance of this compound in different species of sponge may indicate that it is produced by a symbiote.

The biological activity of Halichondrin B is amazing. When evaluated against B-16 melanoma cells it was found to have an IC50 of 0.093ng/mL. Against various cancers, generated in mice, it was shown to be affective at a daily dose of 5ug/kg, which resulted in a doubling of the survival rate. It has also been demonstrated that Halichondrin acts as a microtubule destabiliser and mitoitic spindle poison. It was proven that it is has tremendous in vivo activity against a variety of drug resistant cancers, lung, colon, breast, ovarian to mention a few. Consequently the National Cancer Institute selected it for pre-clinical trials and it’s here that the problems began. According to reference 1 the entire clinical development would require some 10g, and if successful the annual production amount would be between 1-5 kg. Blunt and co-workers managed to isolate 310mg from 1000kg-harvested sponge therefore, the only way to obtain the amounts required is total chemical synthesis. But synthesising 1-5 kg of such a compound would indeed be a mammoth task.

Kishi synthesised this compound7 in 1992 starting from carbohydrate precursors employing the Nozaki-Hiyama-Kishi Ni/Cr reaction, several times, in the long synthetic sequence8, 9. Now as an aside I have used this reaction on scale several times and although it works well its success is very dependant upon the quality of the chromium source and also the presence of other trace transition metals.

In collaboration with Eisai work on the SAR of Halichondrin began. They had a good start: Thanks to the total syntheses of Kishi several advanced intermediates were available for biological screening and one popped out of the screen as being very active:

 

 The first active lead compound

As one can see the complete left hand side of Halichondrin has gone! However, this compound was not active in vivo. Many derivatives and analogues of this compound were prepared: furans, diols, ketones and so on and a lead emerged from this complex SAR study, ER-076349. The vicinal diol was used as a handle for further refinement and lead ultimately to E7389, the clinical candidate.

It can be synthesised in around 35 steps from simple starting materials.

Going through all this work in a few sentences really belittles the tremendous amount of effort that went into discovery and development of this compound and the people involved are to be applauded for their dedication.

Kishi continues to optimise the synthesis of Eribulin as judged by a recent publication10. Where he describes an approach to the amino-alcohol-tetrahydrofuran part of Eribulin (top left fragment, compound 1 below). The retro-synthetic analysis is shown below. The numbering corresponds to that of Eribulin.

The first generation synthesis consisted of 20 steps and delivered compound 1 about 5% yield, the second-generation route was completed in 12 steps with a yield of 48%. One of the highlights includes a remarkable asymmetric hydrogenation11 with Crabtree’s catalyst12:

 

This selectivity was not just luck; it seems to quite general, at least in this system. I always wonder how long it took them to stumble across this catalyst, but then I suppose that Eisai like most of the large pharma. companies has a hydrogenation group that probably indulges in catalyst screening.

The C34-C35 diol was obtained by a Sharpless asymmetric hydroxylation, here the diastereoisomeric ratio was not very high, only about 3:1 in favour of the desired isomer. Fortunately the undesired isomer could be removed completely by crystallisation.

This is a remarkable story and references 1 and 2 are worth reading to obtain the complete picture and learn lots of new chemistry as well. Eisai filed a NDA and the FDA approved the compound in 2010 for the treatment of metastatic breast cancer.

References:

  1. Jackson, K. L., Henderson, J. A., Phillips, A. J., Chem. Rev., 2009, 109, 3044-3079.
  2. Yu, M. J. Kishi, Y., Littlefield, B. A., in Anticancer Agents from Natural Products, page 241; Editors Cragg, G. M., Kingston, D. G. I., and Newmann, D. J. Published by CRC press, Taylor and Francis group, Boca Raton, 2005. ISBM 10:0-8493-1863-7.
  3. Lake, R. J. Internal Report, University of Canterbury, February 26, 1988.
  4. Litaudon, M.; Hart, J. B.; Blunt, J. W.; Lake, R. J.; Munro, M. H. G. Tetrahedron Lett. 1994, 35, 9435.
  5. Litaudon, M.; Hickford, S. J. H.; Lill, R. E.; Lake, R. J.; Blunt,J. W.; Munro, M. H. G. J. Org. Chem. 1997, 62, 1868.
  6. Pettit, G. R.; Herald, C. L.; Boyd, M. R.; Leet, J. E.; Dufresne, C.; Doubek, D. L.; Schmidt, J. M.; Cerny, R. L.; Hooper, J. N. A.; Rutzler, K. C. J. Med. Chem. 1991, 34, 3339.
  7. Aicher, T. D.; Buszek, K. R.; Fang, F. G.; Forsyth, C. J.; Jung, S. H.; Kishi, Y.; Matelich, M. C.; Scola, P. M.; Spero, D. M.; Yoon, S. K. J. Am. Chem. Soc. 1992, 114, 3162.
  8. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281.
  9. (a) Jin, H.; Uenishi, J.; Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. (b) Kishi, Y. Pure Appl. Chem. 1992, 64, 343.
  10. Yang, Yu-Rong, Kim Dae-Shik and Kishi Yoshito, Org. Lett., 2009, 11 (20), 4516–4519.
  11. Stork, G.; Kahne, D. E. J. Am. Chem. Soc. 1983, 105, 1072.
  12. Crabtree, R. H.; Felkin, H.; Fellebeen-Khan, T.; Morris, G. E. J. Organomet. Chem. 1979, 168, 183.
  13.  http://www.drugs.com/halaven.html
By September 15, 2012 4 comments general chemistry, synthetic chemistry

Natural Product Man

Brandon Findlay recently blogged here about “good research and total synthesis” Well here is something I hope he will enjoy.

I recently became aware that a good friend of mine, Professor Stephen Hanessian, of the University of Montreal in Canada, has been awarded the ACS 2012 Ernest Guenther Award in Natural Products Chemistry. His career spans some 45 years, starting as an industrial research chemist and continuing as a still-active academic 45 years later. As he puts it “I remain an ardent student of our profession. I am motivated by the exhilaration of discovery and the creative possibilities that organic synthesis offers.”

Congratulations Steve.

Very recently he published a JOC perspective in which he outlined his philosophy towards natural product synthesis with a myriad of examples of his own work1. I would like to try and give you all a flavor of his approach here.

Amongst other things Prof. Hanessian is probably well known for his propagation of “The Chiron Approach” to organic synthesis2-6. A chiron is a combination of the words chiral and synthon and represents a small chiral building block, for example, amino acids, terpenes, carbohydrates. This gave rise to an excellent computer assisted synthesis program that recognised these chirons in a complex molecule and suggested synthetic routes. I have used this program personally and found it very helpful for the problem I had at the time. This whole approach is based upon a “visual relational thought process” which is a vital part in the planning and conception of the synthesis of a complex molecule.

Let us examine just some of the extensive number of examples given by Prof. Hanessian in his perspective one, for example, Ionomycin.

The calcium salt of this compound is the folded structure A and looks quite complicated, when one “unfolds it” to a linear sequence, compound B, the stereochemical perspective is much more recognisable, however still a very complex molecule.

 

With a good knowledge of organic chemistry and what one can do experimentally, Professor Hanessian reduced compound B to simple chirons, one of which is glutamic acid a simple cheap readily available chiral starting material. This was then converted to some more advanced intermediates en-route to Ionomycin. It would have taken me a long time to get to glutamic acid as a starting material for the synthesis of this compound.

Chiral C2-symmetric phosphonamides are also a significant part of Prof. Hanessian’s contribution to organic chemistry7,8. These compounds are single diastereoisomers where attack of an electrophile occurs from the less hindered side of the anion. Further reaction, in this variant of the Horner-Emmons, reaction leads to the chiral olefins in good yield and high enantiomeric excess. He is still working hard as judged by his latest publication in Organic Letters9, which I can recommend.

I collaborated with Professor Hanessian for many many years during my industrial sojourn. I always enjoyed his visits to the company; not only for the good food and wine we were presented with but for the stimulating chemical discussions and the new perspectives that he brought to a problem. He made us think and he always enjoyed a lively discussion. Congratulations again on your recognition Stephen.

References

  1. Hanessian, S., J. Org. Chem, 2012, dx.doi.org/10.1021/jo300902m
  2. Hanessian, S.; Giroux, S.; Merner, B. L.;Design and Strategy in Organic Synthesis: From the Chiron Approach to Catalysis; Wiley-VCH: Weinheim, 2012.
  3. Hanessian, S.; Franco, J.; Larouche, B. Pure Appl. Chem. 1990, 62, 1887.
  4. Hanessian, S. Reflections on the Total Synthesis of Natural Products: Art, Craft, Logic, and the Chiron Approach. Pure. Appl. Chem., 1993, 65, 1189.
  5. Hanessian, S. Design and Implementation of Tactically Novel Strategies for Stereochemical Control Using the Chiron Approach. Aldrichimica Acta  1989, 22, 3.
  6. Hanessian, S. Total Synthesis of Natural Products: The “Chiron Approach”; Pergamon: Oxford, 1984.
  7. Hanessian, S.; Delorme, D.; Beaudoin, S.; Leblanc, Y. J. Am. Chem. Soc. 1984, 106, 5754.
  8. Bennani, Y. L.; Hanessian, S. Chem. Rev. 1997, 97, 3161.
  9. Hanessian S., Chénard E., Org. Lett., 2012, 14(12), 3222-3225.
By July 18, 2012 3 comments synthetic chemistry